Bendamustine is one species of nitrogen mustards. It has the chemical name: 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid, with the following structure (Formula I):

Bendamustine was initially synthesized in 1963 in the German Democratic Republic and was available under the name ‘Cytostasan’. Bendamustine received its first marketing approval in Germany, where it is marketed under the tradename Ribomustin®. It was indicated as a single-agent or in combination with other anti-cancer agents for a number of cancers including leukemia, Hodgkin's disease, and multiple myelomas. Bendamustine is the active ingredient of the commercial drug product Treanda®, a lyophilized powder for reconstitution. Treanda® is approved by U.S. FDA for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.
Bendamustine is a white to off-white, water soluble microcrystalline powder with amphoteric properties. Bendamustine and its salts are not stable in water. In aqueous solutions, bendamustine and its salts rapidly hydrolyze by direct substitution, leading to three main degradation impurities: a monohydroxy compound (Formula II) (the main degradant), a dihydroxy compound (Formula III), and rarely, a dimer compound (Formula IV), with the following structures:

For this reason, bendamustine and its salts are not suitable for long-term storage in an aqueous solution form. Bendamustine in a solid form has improved chemical stability. The commercial product, Treanda®, is supplied as a sterile non-pyrogenic lyophilized powder in a single-use sealed vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. Prior to use, the vial is opened and reconstituted with 5 mL or 20 mL of Sterile Water for Injection, USP, and further diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, to form a reconstituted solution with a concentration of bendamustine HCl between 0.2 mg/mL and 0.6 mg/mL. The reconstituted solution should be administrated to a patient within 30 minutes because bendamustine undergoes rapid degradation upon reconstitution, producing substantially the same main degradants (Formulas II to IV). Any unused solution should be discarded according to institutional procedures for antineoplastics.
Lyophilized bendamustine compositions are disclosed in U.S. Pat. Nos. 8,436,190, 8,461,350, 8,609,863 and 8,791,270, of the same patent family, the teachings of which are incorporated herein by reference. The patents provide methods of producing lyophilized bendamustine compositions suitable for pharmaceutical drug uses. The methods comprise the step of lyophilizing a pharmaceutical composition containing bendamustine or bendamustine hydrochloride, mannitol, water, and a solvent selected from ethanol, n-propanol, n-butanol, t-butanol (a.k.a., tert-butyl alcohol, or TBA), isopropanol, methanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, acetone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and a combination thereof. However, the patents teach 30% TBA in water as the only solvent system that produces an acceptable lyophilate capable to be reconstituted within 3-5 minutes. Reconstitution of a lyophilate from other solvent systems is difficult and may take more than 45 minutes, which is unacceptable because the bendamustine aqueous mixture may partially degrade. But the lyophilization method using a composition having 30% TBA is not ideal because the lyophilized pharmaceutical compositions may contain a trace amount of t-butanol and up to 0.9% of the monohydroxy degradation byproduct upon reconstitution. Moreover, the lyophilized pharmaceutical compositions may additionally contain bendamustine esters as impurities.
Not all bendamustine and its pharmaceutical salts in a solid form are stable. It is reported that solid anhydrous bendamustine HCl, the form stored in Treanda® vials, may not be stable depending on how it is prepared and stored. U.S. Pat. No. 8,669,279 discloses that solid anhydrous bendamustine hydrochloride degrades after 2 months of storage at 25° C.
Bendamustine compositions in a non-aqueous liquid form for lyophilization or long term storage have been disclosed. German Patent No. 159289 reports that a propylene glycol solution of bendamustine HCl in the presence of an inert gas shows reasonable stability. But such report was recently challenged by U.S. Application Publication No. 20130210879, which discloses that a composition containing bendamustine and propylene glycol shows multiple impurities.
In U.S. Pat. No. 8,344,006, a bendamustine HCl formulation is prepared by solubilizing the drug in a solvent mixture of N,N-dimethylacetamide (also known as N,N-DMA or DMA) and propylene glycol. It shows that a solution of bendamustine in propylene glycol significantly degrades upon standing at room temperature but the addition of propylene glycol is necessary to improve the solubility of bendamustine in the solvent mixture. A solution of bendamustine HCl in N,N-dimethylacetamide is relatively stable. A preferred formulation is bendamustine HCl in a solvent mixture of 66% N,N-DMA and 34% propylene glycol.
In U.S. Pat. No. 8,609,707, a bendamustine HCl liquid formulation is prepared by solubilizing the drug in polyethylene glycol (PEG) and propylene glycol (PG). The patent discloses that the stability of the resulting formulation is improved by adding an antioxidant. Bendamustine is poorly soluble in PEG alone. There is also a risk of freezing and precipitation of the drug product at or below room temperature since the melting point of PEG is near room temperature. To mitigate the technical issues, PG is added. While a higher concentration of PG improves the solubility, it significantly decreases the stability of the formulation. To balance solubility and stability of the formulation, only a small percent of propylene glycol is presented in the solvent mixture.
There is a need for liquid bendamustine formulations which have better stability and impurity profiles than the liquid bendamustine formulations currently available.